PDBsum entry 1q4j

Transferase

PDB id: 1q4j

Contents

Protein chains

209 a.a. *

Ligands

GTX ×2

Waters ×139

* Residue conservation analysis

PDB id:

1q4j

Name:

Transferase

Title:

Crystal structure of pf-gst1 with its inhibitor s-hexyl-gsh

Structure:

Glutathione s-transferase. Chain: a, b. Synonym: pf-gst1. Engineered: yes

Source:

Plasmodium falciparum. Malaria parasite p. Falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Tetramer (from PQS)

Resolution:

2.20Å R-factor: 0.213 R-free: 0.258

Authors:

M.Perbandt,C.Betzel,E.Liebau

Key ref:

M.Perbandt et al. (2004). Native and inhibited structure of a Mu class-related glutathione S-transferase from Plasmodium falciparum. J Biol Chem, 279, 1336-1342. PubMed id: 12972411 DOI: 10.1074/jbc.M309663200

Date:

04-Aug-03 Release date: 25-Nov-03

Protein chains

Q8ILQ7  (GST_PLAF7) -  Glutathione S-transferase from Plasmodium falciparum (isolate 3D7)

Seq: 211 a.a.

Struc: 209 a.a.

Enzyme reactions

• Enzyme class: E.C.2.5.1.18 - glutathione transferase.
• Reaction: RX + glutathione = an S-substituted glutathione + a halide anion + H⁺

RX (Bound ligand (Het Group name = GTX) matches with 76.92% similarity) + glutathione = S-substituted glutathione + halide anion + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M309663200

J Biol Chem 279:1336-1342 (2004)

PubMed id: 12972411

Native and inhibited structure of a Mu class-related glutathione S-transferase from Plasmodium falciparum.

M.Perbandt, C.Burmeister, R.D.Walter, C.Betzel, E.Liebau.

ABSTRACT

The parasite Plasmodium falciparum causes malaria tropica, the most prevailing parasitic disease worldwide, with 300-500 million infections and 1.5-2.7 million deaths/year. The emergence of strains resistant to drugs used for prophylaxis and treatment and no vaccine available makes the structural analysis of potential drug targets essential. For that reason, we analyzed the three-dimensional structure of the glutathione S-transferase from P. falciparum (Pf-GST1) in the apoform and in complex with its inhibitor S-hexyl-glutathione. The structures have been analyzed to 2.6 and 2.2 A, respectively. Pf-GST1 shares several structural features with the Mu-type GSTs and is therefore closely related to this class, even though alignments with its members display low sequence identities in the range of 20-33%. Upon S-hexyl-glutathione binding, the overall structure and the glutathione-binding site (G-site) remain almost unchanged with the exception of the flexible C terminus. The detailed comparison of the parasitic enzyme with the human host Mu-class enzyme reveals that, although the overall structure is homologue, the shape of the hydrophobic binding pocket (H-site) differs substantially. In the human enzyme, it is shielded from one side by the large Mu-loop, whereas in Pf-GST1 the Mu-loop is truncated and the space to recognize and bind voluminous substrates is extended. This structural feature can be exploited to support the design of specific and parasite-selective inhibitors.

Selected figure(s)

Figure 3.
FIG. 3. Stereoview of a ball and stick presentation showing the binding of S-hexyl-GSH at the G-site of Pf-GST1. Carbon atoms are colored in gray, nitrogen atoms are in blue, oxygen atoms are in red, and the sulfur of the inhibitor is shown in yellow. Hydrogen-bonding interactions are indicated in dotted green lines. S-hexyl-GSH is highlighted in yellow. The figure was produced by MOLSCRIPT (41).

Figure 5.
FIG. 5. Surface presentation of the G-site, H-site, and the Mu-loop. a, GST1 from P. falciparum with bound S-hexyl-GSH shown as sticks. There are no interactions between the Mu-loop shown in blue and the C-terminal region shown in yellow. b, the corresponding region of the human Mu-class enzyme GST M2-2 (Protein Data Bank code 1HNA [PDB] ) in complex with glutathione-dinitrobenzene (only the GSH portion of the ligand is shown because of a lack of electron density reported previously (36). The Mu-loop and the C-terminal region are connected by distinct molecular interactions, shielding the G- and H-sites against the solvent. The program GRASP (42) was used to produce the figure.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 1336-1342) copyright 2004.

Figures were selected by an automated process.